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1The Center for Neural Computation, 2Cardiology Department and 3Department of Physiology, Hadassah Medical School, and 4Department of Neurobiology, Life Sciences Institute, The Hebrew University, Jerusalem
Submitted 30 July 2007; accepted in final form 9 June 2008
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ABSTRACT |
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-aminobutyric acid release, probably through activation of 5-HT1B receptors. Postsynaptically, serotonin activates a hyperpolarization-activated cation channel, probably via 5-HT1A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed toward restoration of normal serotonin levels in BG nuclei. |
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INTRODUCTION |
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; Kita 2007; Wichmann and Delong 1996). GP function is dominated by GABAergic activity that originates mainly at the striatum and is modulated by dopamine, acetylcholine, and serotonin (Chadha et al. 2000; Hikosaka 2007; Mink 1996; Parent et al. 1981; Querejata et al. 2005). Since -aminobutyric acid (GABA) is the main carrier of information in the BG network, its modulation by serotonin (5-HT) could indicate serotonin involvement in BG-related clinical disorders such as Parkinson's disease (PD; Albin et al. 1989; Delong 1971; Obeso et al. 2000; Wichmann and DeLong 1996). Recent studies suggest that nondopaminergic BG modulatory systems, including the serotoninergic system, are profoundly involved in PD (Brotchie 2005; Lang and Obeso 2004). This feature has also been crucial in the debate regarding the modulation of serotonin levels in PD therapeutic strategy. There are reports that core parkinsonian motor symptoms have been alleviated using serotonin or specific serotoninergic receptor agonists (Bara-Jimenez et al. 2005; Bonuccelli and Del Dotto 2006; Mignon and Wolf 2007) and many studies have shown attenuation of levodopa-induced dyskinesias brought about by serotonin (Bonuccelli and Del Dotto 2006; Brotchie 2005; Nicholson and Brotchie 2002). By contrast, severe extrapyramidal symptoms have been reported in PD patients treated with serotoninergic drugs, mainly antidepressants (Caley 1997; Gony et al. 2003). Thus both theory and practice would benefit from a comprehensive exploration of serotonin electrophysiology in the GP nucleus.
Anatomical and immunohistochemical studies have established a direct anatomical connection between the raphe nucleus and multiple basal ganglia nuclei, including the GP (Parent et al. 1981; Steinbusch 1981). The serotoninergic effect on pallidal cells is mediated by various 5-HT receptors, including 5-HT1B (Sari et al. 1999, 2004), 5-HT1A (Kia et al. 1996; Pazos and Palacios 1985; Waeber and Moskowitz 1995; Wright et al. 1995), and 5-HT4 (Compan et al. 1996; Vilaro et al. 2005). Contradictory reports on 5-HT2C and 5-HT7 receptors preclude a firm conclusion regarding their presence in the BG and particularly in the GP. There are some claims that 5-HT2C receptors exist in the GP (Appel et al. 1990; Kita et al. 2007); however, other studies indicate that these receptors exist in BG nuclei including striatum and substantia nigra pars reticulata but not in the GP (Compan et al. 1998; Eberle-Wang et al. 1997; Mengod et al. 1990). Contrary to previous data (Neumaier et al. 2001; To et al. 1995), recent studies using new tracers for 5-HT7 receptors have not confirmed their presence in rat GP (Bonaventure et al. 2002). However, there is a general consensus that the most prevalent BG serotonin receptors are the 5-HT1B receptors, located at the presynaptic striatopallidal GABAergic terminals (Sari 2004; Sari et al. 1999; Verge and Calas 2000). In fact, the GP contains the highest proportion of this receptor within the telencephalon (Querejata et al. 2005; Verge and Calas 2000). Lesions of the striatum reveal a marked decrease in 5-HT1B immunoreactivity in the ipsilateral GP, thus supporting their striatal origin (Sari et al. 1999; Schwartz and Coyle 1977). 5-HT4 receptors are located on the somata of striatal cells and also on axonal terminals of striatopallidal fibers (Compan et al. 1996; Vilaro et al. 2005). The subcellular distribution of 5-HT1A receptors in rat GP is still not known.
5-HT receptors are known to function as both auto- and heteroreceptors, affecting serotoninergic axons and nonserotoninergic structures, respectively (Sari et al. 1999, 2004). The heteroreceptor function of 5-HT receptors is mediated by both presynaptic and postsynaptic effects. Presynaptic modulation of GABA release has been reported in many basal ganglia nuclei (Johnson et al. 1992; Stanford and Lacey 1996). Several lines of evidence suggest that presynaptic activation of the 5-HT1B receptor in the GP decreases GABA release. Direct measurement of H3-GABA release from GP slices shows a decrease after 5-HT1B activation (Chadha et al. 2000). An increase in GP firing rate was measured after intrapallidal injection of serotonin, 5-HT1B agonist (Querejeta et al. 2005), or after intravenous injection of fluoxetin, a serotonin reuptake inhibitor, in anesthetized rats (Bergstrom and Walters 1981). Finally, in vivo intrapallidal injection of 5-HT1B receptor agonist was shown to reverse akinesia caused by striatopallidal GABAergic overactivity in parkinsonian states (Chadha et al. 2000). Thus the presynaptic effect of the 5-HT1B receptor on GP neurons is well established, although it has not been directly demonstrated by biophysical methods.
A postsynaptic serotoninergic impact on neuronal excitability has also been suggested (Bickmeyer et al. 2002; Iwahori et al. 2002; Jiang et al. 2000; Kita et al. 2007; Villalobos et al. 2005). Most studies show regulation of postsynaptic h-current (Ih) by serotonin (Bickmeyer et al. 2002; Cardenas et al. 1999; Iwahori et al. 2002), although others have pointed to postsynaptic regulation of other channels as well (Bickmeyer et al. 2002; Jiang et al. 2000; Villabolos et al. 2005). A direct serotoninergic postsynaptic effect on the GP was suggested only recently (Chen et al. 2008; Kita et al. 2007).
To better circumscribe the effect of serotonin and its possible involvement in PD, we studied the effect of serotonin on GP neurons in vitro. We used whole cell recordings of pallidal activity in GP brain slices that enable bath application of serotonin as well as electrical stimulation of the striatum. Thus the postsynaptic effect could be directly measured, whereas the presynaptic effect could be deduced from the responses to striatal stimulation. Our results indicate that serotonin excites GP cells both pre- and postsynaptically. Presynaptically, serotonin attenuates the release of GABA from presynaptic terminals, whereas postsynaptically it depolarizes the GP cell membrane potential and decreases its input resistance, probably by activation of Ih.
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METHODS |
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Rats (10–16 days old) were anesthetized with ether and then decapitated. The brains were rapidly removed and placed in ice-cold Ringer solution (composition in mM: 124 NaCl, 5 KCl, 1.3 MgSO4, 1.2 KH2PO4, 26 NaHCO3, 10 glucose, 2.4 CaCl2, saturated with 95% O2-5% CO2, pH 7.4 at room temperature). A block containing most of the striatum and GP was isolated and 300-µM parasagittal slices were cut using a microslicer (VT-1000, Leica, Leitz, Germany). The slices were then incubated with oxygenated Ringer solution and maintained at 30°C. After 1–2 h of incubation the slices were transferred to a recording chamber and maintained at 35°C under continuous superfusion with the oxygenated Ringer solution. Housing and surgical procedures were in accordance with the Hebrew University Institutional Animal Care and Use committee guidelines.
Intra- and extracellular recordings
Intracellular whole cell patch-clamp recordings were obtained using glass pipettes (10–12 M
) pulled on a Narishige pp-83 puller filled with an intracellular solution (composition in mM: 140 K-gluconate, 4.0 NaCl, 0.5 CaCl2, 5.0 EGTA, 3.0 Mg-ATP, 10 HEPES, and adjusted to pH 7.3 with KOH). Neurons were visualized using differential interference contrast infrared microscopy (Zeiss, Oberkochen, Germany; Hamamatsu c-2400, Shizouka, Japan). GP cells were selected on the basis of their location, soma size, and shape (Rav-Acha et al. 2005). Membrane current and voltage were recorded using Axopatch 1D or Axoclamp 2A amplifiers (Axon Instruments, Foster City, CA), in the conventional bridge voltage-clamp or current-clamp mode, respectively.
A bipolar stimulating electrode driven by 0.1-ms pulse (Master 8, AMPI, Jerusalem, Israel; isolation unit, Mk4 Devices, London, UK) was used to stimulate the presynaptic axons. The stimulating electrode was advanced under visual control and placed in the center of the striatum. To facilitate striatal stimulation we used parasagittal slices oriented parallel to the striatopallidal fibers (Rav-Acha et al. 2005).
For extracellular recording, the electrodes were filled with the above-described Ringer solution and the signals were recorded in current-clamp mode. Cells were identified as with the intracellular recordings and the electrodes were placed in close contact with the cell membrane without forming a seal. Stable recordings were characterized by a regular firing frequency and spike pattern for 
10 min prior to initiating the experiment.
The data were sampled at a rate of 10 kHz with a National Instrument board driven by LabVIEW (National Instruments, Austin, TX) based homemade software that was used for on- and off-line analysis.
Drugs
5-Hydroxytryptamine (5-HT; serotonin creatinine-sulfate complex; Sigma, Poole, UK) was added to the physiological Ringer solution (20–50 µM final bath concentrations). We recorded the effects of serotonin 20 min after its addition to the experimental bath. Complete recovery was obtained only after a prolonged wash period (
80 min). 7-Trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo-[1,2-a]quinoxa line maleate (CGS-12066A, Sigma), a specific 5-HT1B receptor agonist (10 µM), and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide trihydrochloride (Way-100635, Sigma), a specific 5-HT1A receptor antagonist (1–5 µM), were used to explore the specific effects of these receptors on GP cells. 4-(N-Ethyl-N-phenylamino-1,2-dimethyl-6-methylamino)pyrimidinium chloride (ZD 7288, 10–100 µM), a specific h-current blocker, was used to study the h-current contribution to GP cell properties. Gabazine (10 µM) was used to block GABAA receptors. All drug effects were examined 20 min after their addition to the experimental bath.
Data analysis
The current–voltage (I–V) relations were measured by averaging the voltage response to hyperpolarized and depolarized step currents. Average postsynaptic potentials evoked by striatal stimulation, recorded via current-clamp mode, were measured at a membrane potential of –80 mV. The spontaneous synaptic currents, recorded via voltage-clamp mode, were detected and segregated from "noise" by an amplitude threshold of 0.02 nA and a half-amplitude duration threshold of 10 ms. The frequency dependence of the synaptic currents was estimated by averaging the synaptic response of GP cells to striatal train stimuli at various intratrain frequencies.
Analysis of extracellular recordings, which included calculating the mean firing frequency, the interspike interval (ISI) histograms, and the autocorrelation functions, was carried out on Matlab programs (Matlab V7.2, MathWorks, Natick, MA). The changes in firing frequency were described by their percentile change relative to the firing frequency in the control condition. The rhythmicity index (RI) was used to quantify the rhythmicity of the firing (Long et al. 2004). The index was calculated from the power spectrum density (using the P Welch algorithm) of the spike trains. The integral under the peak of the characteristic frequency was calculated using different integration windows (with widths ranging from 0.5 to 5 Hz) and normalized by the total power [from 0 to 1/(minimal (ISI) Hz)]. Thus a pure sinusoidal process will have a value of RI = 1, whereas a purely random process will have a value of RI very close to zero.
Statistics
Numerical data in the text are expressed as the means ± SD. The statistical significance of data comparing the results of two groups of identical populations of GP cells was done using paired two-tailed t-test. When more than two groups were tested, we used a two-factor ANOVA without replication to test for differences between groups.
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RESULTS |
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The effect of serotonin on GP firing pattern was first analyzed by monitoring the extracellular expression of neuronal activity. Single-unit activity was characterized by a biphasic waveform lasting for 3.5 ± 0.8 ms and dominated by the positive phase that reached average amplitude of 3.8 ± 1.8 mV. All extracellular GP recordings (n = 25) revealed regular spontaneous firing at a frequency of 2–20 Hz (6.5 ± 4.5 Hz). The ISI displayed a narrow distribution and the RI was 0.61 ± 0.12 (n = 25) (Fig. 1).
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The dose–response curve of the serotonin effect was examined in 10 cells. An example is shown in Fig. 2A, where the firing rate gradually increased as a function of the serotonin concentration reaching saturation at a frequency of 10 Hz. The normalized average firing response of 10 cells is shown in Fig. 2B, which shows that 90% saturation was reached at a concentration of 20 µM. Thus the serotonin concentration (30 µM) used in most of our experiments was well above the saturation of the GP cell response to serotonin.
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Serotonin 1B receptors (5-HT1B) are densely expressed over the striatopallidal terminals and were shown to regulate presynaptic GABA release (Chadha et al. 2000; Querejeta et al. 2005; Sari et al. 1999). Therefore we examined the effects of CGS-12066A, a specific 5-HT1B agonist, on the spontaneous spike trains of GP neurons. CGS-12066A reversibly increased GP firing rate; however, its effect was smaller than that induced by serotonin (Fig. 3). On average, CGS-12066A (10 µM) increased the firing frequency of GP neurons by 22 ± 11% (from 6.2 ± 3.1 to 8.1 ± 3.7 Hz; n = 5, P < 0.05, t-test), whereas in these cells, the application of serotonin (30 µM) alone increased firing frequency by 77 ± 32% (from 6.2 ± 3.1 to 11 ± 4 Hz; n = 5, P < 0.05, t-test). The firing increase induced by serotonin was significantly larger than that induced by 5-HT1B agonist (n = 5, P < 0.05, ANOVA).
Since 5-HT1B receptors in the GP are located on the GABAergic terminals and are likely to mediate their effect by modulating the release of GABA (Sari 2004; Sari et al. 1999), we examined how blocking GABAA receptors (by gabazine) would affect the response of GP neurons to serotonin. Recall that the GABAergic receptors on GP cells consist of both GABAA and GABAB receptors (Kaneda and Kita 2005; Kita 1992; Kita et al. 2005; Stanford and Cooper 1999). However, the activation of GABAB receptors was shown to be induced by GP GABAergic collaterals and not by striatopallidal afferents (Kita et al. 2005). Thus 5-HT1B receptors located on striatopallidal terminals (Sari 2004; Verge and Calas 2000) should mainly induce GABAA-mediated responses. Gabazine (10 µM) increased the firing frequency of GP cells by 21 ± 10% (Fig. 3; from 5.6 ± 2.7 to 7.2 ± 3.1 Hz; n = 7, P < 0.05, t-test), whereas serotonin (30–40 µM) in the presence of gabazine further increased firing frequency by 29 ± 7.6% (from 7.2 ± 3.1 to 9.5 ± 3.6 Hz; n = 7, P < 0.05, ANOVA). It is thus likely that serotonin also has an excitatory postsynaptic effect. The addition of 5-HT1A blocker to serotonin in the presence of gabazine practically restored the original firing rate of the GP cells. The control firing frequency of 5 ± 1.8 Hz increased to 8.2 ± 3.2 Hz after the addition of gabazine + serotonin, and decreased to virtually the control value of 5.3 ± 2.1 Hz in the presence of gabazine + serotonin + 5-HT1A antagonist (n = 3). Thus we suggest that 5-HT1A receptors are involved in serotonin's postsynaptic effect.
A summary of the effects of serotonin and the various drugs on GP activity, measured via extracellular recording, appears in Fig. 3. The effects of the various drugs are described as their relative effect compared with control condition. The effects of serotonin in the presence of 5-HT1A blocker, the effect of 5-HT1B agonist, and the effect of gabazine are comparable. Thus this figure demonstrates that 5-HT1A and 5-HT1B activation can account for most of the effects of serotonin on GP cells.
Considering the fact that in our GP slices the subthalamic nucleus (STN)–GP connection was severed—and therefore the main afferent input to GP cells consisted of GABAergic striatopallidal afferents and pallidopallidal axonal collaterals—our extracellular recordings suggest that serotonin has both pre- and postsynaptic excitatory influences on GP cells. In reaching this conclusion, which is in line with previous studies, we assume that the glutamatergic STN input does not exist in our slice preparation. Thus the fact that serotonin excites GP neurons even in the presence of gabazine mandates a postsynaptic effect. The presynaptic effect of serotonin is suggested by the observation that gabazine reduces the effect of serotonin. It is reasonable to assume that this presynaptic effect is mediated by the 5-HT1B receptors and that the activation of 5-HT1A receptors is involved in the postsynaptic effect. To unravel the biophysical mechanism that underlies serotonin's effect and to examine its putative combined pre- and postsynaptic source, we analyzed the changes in the membrane properties of GP cells by using whole cell patch-clamp recordings from pallidal neurons.
Intracellular recordings from GP neurons
Stable intracellular recordings were obtained from 50 pallidal neurons. We used the same criteria as those of a previous work (Rav-Acha et al. 2005). Accordingly, pallidal neurons that were included in this study had a resting potential more negative than –45 mV, a spike amplitude >50 mV, and presented stable recording for 40 min. The average quiescent membrane potential and input resistance was –56 ± 6.4 mV and 524 ± 156 M, respectively (n = 50). The mean threshold was –46 ± 5 mV and spike amplitude 63 ± 8.7 mV. Similar to the extracellular recordings, most (75%) of these cells exhibited regular spontaneous rhythmic firing at 2–20 Hz (8.4 ± 4 Hz). The cells were characterized by time- and voltage-gated anomalous rectification followed by a rebound potential in response to hyperpolarizing step currents.
Postsynaptic effect of serotonin: reduction in input resistance and increased excitability
Serotonin at a concentration of 20–50 µM (30 ± 10 µM) depolarized the membrane potential and increased the membrane conductance. As shown in Fig. 4, under normal conditions (Fig. 4A) the membrane voltage partially repolarized during negative current injection (Fig. 4A, single arrow). This response, known as "sagging," reflects the activation of an h-like current. This type of current, which is carried by sodium and potassium ions, is activated by hyperpolarization beyond –50 to –70 mV. The activation of this current slowly depolarizes the cell toward an equilibrium potential of approximately –30 mV (Pape 1996). In fact, adding Cs ions or ZD 7288 to the extracellular solution completely and reversibly blocked this response (data not shown). As expected from the slow kinetics of the h-current, the hyperpolarizing response was followed by rebound depolarization (Fig. 4A, double arrow). The addition of serotonin (30 µM) depolarized the membrane potential from –65 to –59 mV and decreased the input resistance from 700 to 290 M (Fig. 4B). An average depolarization of 10.3 ± 5.1 mV from –58.9 ± 6.4 to –48.6 ± 5.3 mV and a 43 ± 15.8% decrease in input resistance from 544 ± 173 to 312 ± 147 M were calculated across the population of cells (n = 35, P < 0.01, t-test). Interestingly, serotonin also attenuated the sagging response to hyperpolarized currents. As shown in Fig. 4C these effects were mostly reversible. The decrease in input resistance was further analyzed by comparing the I–V curves before and after addition of serotonin (Fig. 4, D and E, respectively). The significant decrease in the slope of the I–V curve after addition of serotonin corroborated the reduction in input resistance. It is interesting to note that the two curves intersect at –35 mV, close to the h-current reversal potential (Fig. 4F) (Pape 1996). An average intersection point of –32 ± 4.7 mV was calculated for 30 cells. The attenuated sagging in the response to hyperpolarizing step currents and the comparable reversal potential suggest that serotonin either blocks or continuously activates the h-current. Thereafter, the decreased input resistance induced by serotonin suggests continuous Ih activation.
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, whereas adding ZD 7288 (70 µM; Fig. 5C) increased the input resistance to 1,000 M. The resting membrane potential, –60 mV, was depolarized by serotonin to –51 mV and hyperpolarized to –65 mV after the addition of ZD 7288. On the population level we analyzed nine cells where the addition of serotonin was followed by the blockade of Ih with ZD 7288 (10–100 µM). In these experiments serotonin (30 µM) depolarized the cells from –61 ± 4.8 to –51 ± 2.9 mV and decreased the input resistance from 610 ± 160 to 344 ± 80 M. Under these conditions ZD 7288 hyperpolarized the cells to –65 ± 6.2 mV and increased the input resistance to 684 ± 182 M (n = 9, P < 0.05, ANOVA). Finally, the effects of serotonin were prevented by previously blocking the h-current. This is shown for another GP cell in Fig. 5, D–F where ZD 7288 increased the input resistance from 420 to 570 M (Fig. 5, D and E), whereas the addition of serotonin after ZD 7288 had only a slight effect (Fig. 5F). Similar effects were observed in three cells where ZD 7288 (50 µM) increased the input resistance from 410 ± 32 to 490 ± 45 M, whereas the addition of serotonin after ZD 7288 decreased the input resistance to 479 ± 37 M (nonsignificant effect). Thus we suggest that the postsynaptic effect of serotonin on GP cells is mediated by activation of Ih, which has a major influence on GP activity (Chan et al. 2004).
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The spontaneous and evoked GABAergic synaptic potentials recorded from GP neurons were used to characterize the presynaptic effect of serotonin. Stimulating the striatal area evoked an inhibitory postsynaptic potential (IPSP) in GP neurons. These synaptic events appeared after a delay of 5.75 ± 1.18 ms, had a mean duration at half-amplitude of 38 ± 13 ms, and their average reversal potential was –63 ± 6.3 mV (Fig. 6, A and C; n = 12). The latter is consistent with the expected reversal potential of the GABAA receptors (Rav-Acha et al. 2005). Serotonin (30 µM) decreased the amplitude of the PSP by 78% (from 9.5 to 2 mV) and shortened the duration at half-amplitude by 26% (30 to 22 ms) (Fig. 6B). The reversal potential of the evoked PSP was unaffected by serotonin (–63 mV; Fig. 6, compare A with B). The average reduction of the PSP amplitude caused by serotonin (30 µM) was 54 ± 16% (from 8.6 ± 2.6 to 4.1 ± 1.8 mV) and the duration at half-amplitude was shortened by 21 ± 11% (from 38 ± 13 to 30 ± 11 ms), whereas the average reversal potential was –63 ± 6.3 mV and was unaffected by serotonin (n = 12, P < 0.05, t-test).
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We further investigated this possibility by directly measuring the synaptic current, via voltage-clamp mode, which under some circumstances is independent of the membrane resistance. The superimposed traces in Fig. 6D show the synaptic currents before (black trace) and after (red trace) the addition of serotonin (30 µM). Serotonin decreased the synaptic current amplitude by 45%, further supporting direct inhibition of GABA release. An average reduction of the synaptic current amplitude by 49 ± 13% (from 0.11 ± 0.04 to 0.058 ± 0.018 nA) was calculated across a population of GP cells (n = 13, P < 0.05, t-test). Finally, we restored the input resistance by blocking the h-current (see preceding text). This was done to block the main postsynaptic effect of serotonin, leaving the presynaptic mechanism intact. Interestingly, in a few experiments where ZD 7288 (100 µM) was added in the presence of serotonin, a further decrease in the evoked synaptic current was observed (Fig. 6D, green trace). This unexpected result confirms that the decrease in PSP amplitude caused by serotonin is independent of its effect on input resistance and raises the possibility that a presynaptic h-current is involved in GABAergic release.
Serotonin decreases the spontaneous inhibitory synaptic activity
The spontaneous synaptic events recorded in vitro in GP neurons are mostly GABAergic, originating either from striatal terminals or GP collaterals. To further examine the presynaptic mechanism of serotonin, we studied its effect on the spontaneous synaptic activity of GP cells. An example of this effect is shown in Fig. 7. The spontaneous synaptic activity in this example had an average amplitude of 0.038 ± 0.013 nA and a frequency of 14.3 ± 5.3 Hz (Fig. 7A), whereas the activity after serotonin application (30 µM) was characterized by an amplitude of 0.029 ± 0.01 nA and a frequency of 8.3 ± 3.2 Hz (Fig. 7B; P < 0.05). The distributions of amplitudes and frequencies of spontaneous synaptic currents in this example are shown in Fig. 7, C and D, respectively. Averaging the results of six cells revealed spontaneous synaptic activity with an amplitude and frequency of 0.045 ± 0.016 nA and 16.5 ± 6.4 Hz, respectively. Serotonin (30 µM) decreased the synaptic amplitude and frequency to 0.032 ± 0.014 nA and 10.6 ± 4.4 Hz, respectively (n = 6, P < 0.05, t-test).
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In our previous work we showed that GP cells are characterized by a frequency-dependent decline of the striatal evoked synaptic response (Rav-Acha et al. 2005). This phenomenon, known as synaptic depression, characterizes many other CNS nuclei (Abbott et al. 1997; O'Donovan and Rinzel 1997). The mechanism underlying depression is a frequency-dependent decrease of transmitter release (Abbott et al. 1997). Since our results indicate that serotonin has a significant presynaptic effect on GABAergic synapses, it could affect the process of synaptic depression. Figure 8 shows the frequency-dependent depression of striatal evoked postsynaptic currents (PSCs). The striatopallidal pathway was stimulated by train stimuli at different frequencies in normal condition (Fig. 8A) and in the presence of 30 µM serotonin (Fig. 8B). The PSC amplitude progressively decreased, reaching steady state after 15–20 stimuli (Fig. 8C). This steady-state level decreased as the intratrain frequency increased. Although a similar depression along the train stimuli was observed when serotonin was presented, the relative depression was smaller. Thus in the control condition during 10-Hz striatal stimulation, the steady-state PSC amplitude decreased to 0.2 of its initial value (Fig. 8C, closed circles), whereas under serotonin it decreased to 0.29 of its initial value (Fig. 8C, open circles). Averaging the results from seven cells revealed that in the control condition during striatal intratrain stimuli of 8 and 20 Hz, the steady-state PSC amplitude decreased to 0.39 ± 0.14 and 0.21 ± 0.06 of its initial value, respectively (Fig. 8D, closed circles). In the presence of serotonin (30 µM), the steady-state PSC amplitude decreased to 0.63 ± 0.17 and 0.47 ± 0.13 of its initial value at the corresponding frequencies of stimulation (Fig. 8D, open circles). These differences induced by serotonin were statistically significant (n = 7, P < 0.05, t-test).
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DISCUSSION |
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) showed that the majority of spontaneously active GP cells were not affected by iontophoretically applied serotonin. Furthermore, 83% of the regularly firing GP cells did not respond to dorsal raphe nucleus stimulation. By contrast, intrapallidal infusion of serotonin (Querejeta et al. 2005) increased the firing of 75% of the pallidal cells of anesthetized rats, decreased the firing in 12.5%, and had no effect in another 12.5%. A different distribution of the responding cells was obtained with intravenous injection of serotonin uptake inhibitor, where 43% of the cells increased their firing rate and another 43% were unaffected (Bergstrom and Walters 1981). A recent extracellular in vivo study of awake monkeys showed an almost equal distribution of increased and decreased firing of GPe (external segment of the globus pallidus) cells induced by local application of serotonin, with no change in mean firing rate of the total GPe group (Kita et al. 2007). These results were used to suggest that the suppression of GABAergic release from striatal–GP terminals on one hand and suppression of excitatory glutatmatergic release from STN–GP terminals on the other are the source of the inconsistency of serotonin's effect (Kita et al. 2007). The need for further examination of the precise electrophysiological effects of serotonin on GP cells prompted the current study. The major findings in this work can be summarized as follows: 1) Serotonin significantly increases the spontaneous firing rate of GP neurons in a slice preparation preserving striatal–GP innervation. 2) The increase in firing rate is due to combined pre- and postsynaptic effects. 3) The postsynaptic effect, which is probably mediated by 5-HT1A receptors, apparently activates the Ih current, thereby depolarizing the neurons and increasing their spontaneous firing rate. 4) The presynaptic effect, which is probably mediated by 5-HT1B receptors, decreases the inhibitory striatopallidal transmission, thereby increasing the spontaneous firing of GP neurons. 5) The reduction of striatopallidal synaptic release leads eventually to a reduction in the process of synaptic depression of this pathway.
These results are basically consistent with a recent publication by Chen et al. (2008), reporting that serotonin has excitatory pre- and postsynaptic effects on GP cells. According to this study the presynaptic effect, which is mediated by 5-HT1B receptors, results from a reduction in the frequency of miniature inhibitory synaptic potentials accompanied by an increased rate of tetrodotoxin (TTX)-sensitive synaptic events. The postsynaptic effect is mediated by 5-HT7 and 5-HT4 receptors. They argue that 5-HT4 receptors activate nonselective cation conductance, whereas the 5-HT7 receptors activate the Ih current. Although we cannot rule out the involvement of these receptors, our results suggest that the 5-HT1A receptors can account for most of the serotonin-driven postsynaptic excitation of GP cells. Notably, some of the above-cited differences could result from the immature rat brain slices used in our study.
Serotonin was found to have both pre- and postsynaptic effects in various CNS nuclei (Bickmeyer et al. 2002; Iwahori et al. 2002; Jiang et al. 2000; Johnson et al. 1992; Stanford and Lacey 1996; Villalobos et al. 2005). Several studies denoted the prominent role of 5-HT1B receptors that are located on the presynaptic GABAergic terminals and exert their excitatory effect on GP cells by decreasing the release of GABA (Chadha et al. 2000; Querejeta et al. 2005; Sari 2004). Recently, a further suppression of presynaptic release of excitatory glutamatergic input by 5-HT1A receptors was suggested (Kita et al. 2007). However, due to the severing of the STN–GP connection in our slice preparation we could not evaluate the serotoninergic influence on the glutamatergic excitatory input.
Contrary to the well-established data regarding presynaptic attenuation of GABAergic release, the possibility of a postsynaptic serotoninergic effect on GP cells was suggested only recently from an in vivo study of awake monkeys (Kita et al. 2007). Kita et al. (2007) suggested a postsynaptic effect via 5-HT1A receptors; however, they report an inhibitory effect rather than an excitatory one as found in our study.
A serotoninergic effect mediated by the Ih current has been described in other brain structures (Bickmeyer et al. 2002; Iwahori et al. 2002; Liu et al. 2003). For example, activation and inhibition of Ih channels in mouse hippocampal neurons were found to be triggered by the activation of somatic and dendritic serotonin receptors, respectively (Bickmeyer et al. 2002). In GP cells, activation of Ih is of particular importance since it is involved in the high-frequency regular pacemaker-like activity of these neurons. Moreover, Ih has been proposed as the mechanism by which striatal input synchronizes GP firing. In fact, blocking Ih markedly decreased GP firing frequency and disrupted GP cell regularity (Chan et al. 2004). Thus it is likely that serotonin modulates GP firing rate and pattern and can potentially rectify abnormal firing and patterns such as those that occur in PD.
Contrary to past decades, where PD was attributed to a dysfunction of the dopaminergic system per se, work over the last decade has increasingly focused on the role of the serotoninergic system in both pathophysiology and treatment of PD (Bonuccelli and Del Dotto 2006; Lang and Obeso 2004; Nicholson and Brotchie 2002). The neurodegenerative process in PD is not limited to the dopaminergic system but rather extends to other neuronal systems as well, including the serotoninergic system (Bonuccelli and Del Dotto 2006; Braak and Braak 2000; Lang and Obeso 2004). Recent data identified the 5-HT1A, 5-HT1B, and 5-HT2C receptors as potential therapeutic targets in advanced PD (Bara-Jimenez et al. 2005; Bonuccelli and Del Dotto 2006; Mignon and Wolf 2007; Nicholson and Brotchie 2002). Furthermore, serotonin has been shown to attenuate the major motor complications of chronic L-DOPA therapy, known as levodopa-induced dyskinesia (Brotchie 2005; Lang and Obeso 2004).
To date, the GP (the primate GPe) is considered a pivotal nucleus in PD. It is commonly accepted that the absence of normal dopaminergic innervation, which occurs in PD, leads to a decrease in firing rate and appearance of pathologic synchronization of GP neurons (Albin et al. 1989; Bergman et al. 1998; Nini et al. 1995; Wichmann and Delong 1996). Thus increasing the firing rate and reducing the synchrony of GP neurons could be used as a possible therapeutic strategy for PD. These two effects are generated by serotonin. We demonstrated here that serotonin increases the GP firing rate and it is likely that part of this effect is due to activation of the Ih current. Although Ih has been suggested as a mechanism by which the inhibitory striatal input synchronizes GP activity (Chan et al. 2004), the activation of the Ih current in a time-independent manner—as we postulate to occur in the presence of serotonin—probably reduces the synchronizing effect of the striatal inhibitory input on GP firing.
Since serotonin has been found to decrease GABA release from GP GABAergic afferents, it was reasonable to expect it to affect time- and frequency-dependent synaptic depression (Rav-Acha et al. 2005). Synaptic depression is usually attributed to depletion of synaptic vesicles caused by high-frequency stimulation (Abbott et al. 1997; O'Donovan and Rinzel 1997). Since serotonin decreases synaptic release it should decrease the rate of synaptic depression. Indeed we found that serotonin decreased the magnitude of this frequency-dependent synaptic depression. The serotoninergic effect on synaptic depression could be important in terms of bradykinesia-related beta-range oscillations, which are commonly observed in the parkinsonian brain (Brown 2006; Hammond et al. 2007; Rivlin-Etzion et al. 2006). The ability of these oscillations to spread around the basal ganglia network is dependent on the low-pass filter properties of these network pathways. The decreased serotonin levels existing in BG nuclei in PD (Di Cara et al. 2003; Halliday et al. 1990) with the resulting enhanced synaptic depression may favor synchronization in the beta range of the frequency domain. Modification of these filter properties, and especially the attenuation of low-pass filtering of the striatopallidal pathway as may be achieved by serotonin replacement therapy for PD, could promote the spread of the high-frequency prokinetic gamma-range oscillations (Brown 2003; Hammond et al. 2007). Thus serotonin could supply another line of defense in the battle for better treatment of PD patients.
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Address for reprint requests and other correspondence: M. Rav-Acha, The Hebrew University, Hadassah Medical School, Cardiology Department, P.O. Box 12272, Jerusalem, Israel 91120 (E-mail: oritmoshe{at}yahoo.com)
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